Efficacy and toxicity of drugs targeting KRAS ^G12C mutation in non-small cell lung cancer: a meta-analysis

ABSTRACTObjective To systematically analyze the efficacy and toxicity of drugs targeting KRASG12C mutation in non-small cell lung cancer (NSCLC).Methods The candidate studies were identified in PubMed, Embase, Cochrane Library, CNKI and Wanfang databases up to 1 June 2023. Data on efficacy, prognosis, and adverse events (AEs) were extracted and calculated by meta-analysis.Results Six eligible prospective studies were included in this meta-analysis, including 563 patients with advanced or metastatic NSCLC. For patients with NSCLC, the objective response rate (ORR) of drugs targeting KRASG12C mutation was 37% (95%CI 31-43), median duration of response (DOR) was 8.89 months (95%CI 7.96-9.83), and median progression-free survival (PFS) was 6.40 months (95%CI 5.86-6.93). The overall incidence of AEs was 88% (95%CI 79-96) and the incidence of grade ≥ 3 AEs was 44% (95%CI 24-64). The most common AEs were diarrhea, nausea, fatigue, and vomiting. The most common grade ≥ 3 AEs were Alaninetransaminase (ALT) or Aspartatetransaminase (AST) increased and diarrhea.Conclusion Sotorasib, Adagrasib, and Garsorasib as the drugs of choice for patients with KRASG12C mutation NSCLC, have definite efficacy and acceptable safety, especially for patients with advanced or metastatic disease and within posterior line therapy.KEYWORDS: KRASG12C mutationnon-small cell lung cancerefficacyprognosisadverse eventsDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. AbbreviationsNSCLC, Non-small cell lung cancer; AEs, Adverse Events; ORR, Objective Response Rate; DCR, Disease control rate; DOR, Duration of response; PFS, Progression-Free Survival; OS, Overall Survival; ALT, Alaninetransaminase; AST, Aspartatetransaminase; GTP, Guanosine triohosphte; GDP, Guanosine diphosphate; CNS, central nervous system; MINORS, Methodological Index for Non-Randomized Studies; 95%CI, 95% confidence intervals; RCT, Randomized Controlled Trial; NE, NE, not evaluable, NA, Not Available; CR, Complete Response; PR, Partial Response.Declaration of InterestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Author Contribution StatementWei Luo, Jing Zhu; These authors contributed equally to this work and should be considered co-first authors. (I) Conception and design: Wei Zhou; (II) Administrative support: Ke Xu and Wei Zhou; (III) Collection and assembly of data: Ke Xu, Wenxue Zhang, and Airu Yu; (IV) Data analysis and interpretation: Ke Xu and Airu Yu; (V) Manuscript writing: Wei Luo and Jing Zhu; (VI) Final approval of manuscript: Wei Luo, Jing Zhu, Wenxue Zhang, Airu Yu, Ke Xu, and Wei Zhou.Reviewer DisclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Fig. 1. Detailed process of literature identification and screening.Display full sizeFig. 2. Pooled analysis of the efficacy and toxicity of the drugs targeting KRASG12C. A. ORR, B. DCR, C. DOR, D. PFS, E. 6-month PFS, F. OS, G. incidence of AEs, H. incidence of ≥3 grade AE.Display full sizeFig. 3. Subgroup analysis of the drugs targeting KRASG12C in patients with advanced or metastatic NSCLC.Display full sizeA-B. Subgroup analysis of ORR and DCR by grouping the studies according to the name of the drug taken. C-D. Subgroup analysis of ORR and DCR by grouping the studies according to the number of the subjects. E-F. Subgroup analysis of ORR and DCR by grouping the studies by ethnicity.Fig. 4. Sensitivity analysis of the efficacy and toxicity of the drugs targeting KRASG12C. A. ORR, B. DCR, C. DOR, D. PFS, E. 6-month PFS, F. OS, G. incidence of AEs, H. incidence of ≥3 grade AEDisplay full sizeFig. 5. Publication bias analysis of the efficacy and toxicity of the drugs targeting KRASG12C. A. ORR, B. DCR, C. DOR, D. PFS, E. 6-month PFS, F. OS, G. incidence of AEs, H. incidence of ≥3 grade AEDisplay full sizeAdditional informationFundingThe project was funded by the Natural Science Foundation of Sichuan Province (Grant No. 2023NSFSC0729), the Natural Science Foundation of The First Affiliated Hospital of Chengdu Medical College (Grant No. CYFY2021YB01), and Key Clinical Specialty of Sichuan Province (2022). The funder had no role in study design, data collection, and analysis, the decision to publish, or the preparation of the manuscript.